bims-ectoca 2022-01-16 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022–01–16
ten papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation.
The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer.
Now open: Evolving insights to the roles of lysine acetylation in chromatin organization and function.
The activity of human enhancers is modulated by the splicing of their associated lncRNAs.
Inhibition of histone demethylase KDM4 by ML324 induces apoptosis through the unfolded protein response and Bim upregulation in hepatocellular carcinoma cells.
Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy.
Role of histone demethylases and histone methyltransferases in triple-negative breast cancer: Epigenetic mnemonics.
The unfavorable clinical outcome of COVID-19 in smokers is mediated by H3K4me3, H3K9me3 and H3K27me3 histone marks.
Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.
Biomechanical model of cells probing the myosin-II-independent mechanosensing mechanism.

Stem Cell Res Ther. 2022 Jan 10. 13(1): 10

Context-dependent transcriptional regulations of YAP/TAZ in stem cell and differentiation.

Juan Luo, Peng Li.

  Hippo pathway is initially identified as a master regulator for cell proliferation and organ size control, and the subsequent researches show this pathway is also involved in development, tissue regeneration and homeostasis, inflammation, immunity and cancer. YAP/TAZ, the downstream effectors of Hippo pathway, usually act as coactivators and are dependent on other transcription factors to mediate their transcriptional outputs. In this review, we will first provide an overview on the core components and regulations of Hippo pathway in mammals, and then systematically summarize the identified transcriptional factors or partners that are responsible for the transcriptional output of YAP/TAZ in stem cell and differentiation. More than that, we will discuss the potential applications and future directions based on these findings.

Keywords:  Context-dependent; Hippo pathway; Stem cell and differentiation; Transcriptional output; YAP/TAZ

DOI:  https://doi.org/10.1186/s13287-021-02686-y
Cancers (Basel). 2021 Dec 21. pii: 6. [Epub ahead of print]14(1):

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer.

Daniela Trisciuoglio, Francesca Degrassi.

  Microtubules are key components of the cytoskeleton of eukaryotic cells. Microtubule dynamic instability together with the "tubulin code" generated by the choice of different α- and β- tubulin isoforms and tubulin post-translational modifications have essential roles in the control of a variety of cellular processes, such as cell shape, cell motility, and intracellular trafficking, that are deregulated in cancer. In this review, we will discuss available evidence that highlights the crucial role of the tubulin code in determining different cancer phenotypes, including metastatic cell migration, drug resistance, and tumor vascularization, and the influence of modulating tubulin-modifying enzymes on cancer cell survival and aggressiveness. We will also discuss the role of post-translationally modified microtubules in autophagy-the lysosomal-mediated cellular degradation pathway-that exerts a dual role in many cancer types, either promoting or suppressing cancer growth. We will give particular emphasis to the role of tubulin post-translational modifications and their regulating enzymes in controlling the different stages of the autophagic process in cancer cells, and consider how the experimental modulation of tubulin-modifying enzymes influences the autophagic process in cancer cells and impacts on cancer cell survival and thereby represents a new and fruitful avenue in cancer therapy.

Keywords:  acetylation; autophagy; cancer; microtubules; tubulin post-translational modifications; tubulin-modifying enzymes; tyrosination

DOI:  https://doi.org/10.3390/cancers14010006
Mol Cell. 2022 Jan 05. pii: S1097-2765(21)01066-2. [Epub ahead of print]

Now open: Evolving insights to the roles of lysine acetylation in chromatin organization and function.

Ying-Jiun C Chen, Evangelia Koutelou, Sharon Y R Dent.

  Protein acetylation is conserved across phylogeny and has been recognized as one of the most prominent post-translational modifications since its discovery nearly 60 years ago. Histone acetylation is an active mark characteristic of open chromatin, but acetylation on specific lysine residues and histone variants occurs in different biological contexts and can confer various outcomes. The significance of acetylation events is indicated by the associations of lysine acetyltransferases, deacetylases, and acetyl-lysine readers with developmental disorders and pathologies. Recent advances have uncovered new roles of acetylation regulators in chromatin-centric events, which emphasize the complexity of these functional networks. In this review, we discuss mechanisms and dynamics of acetylation in chromatin organization and DNA-templated processes, including gene transcription and DNA repair and replication.

Keywords:  DNA repair; DNA replication; acetylation; acetyltransferase; chromatin organization; deacetylase; enhancer; transcription

DOI:  https://doi.org/10.1016/j.molcel.2021.12.004
PLoS Comput Biol. 2022 Jan 11. 18(1): e1009722

The activity of human enhancers is modulated by the splicing of their associated lncRNAs.

Jennifer Yihong Tan, Ana Claudia Marques.

Pervasive enhancer transcription is at the origin of more than half of all long noncoding RNAs in humans. Transcription of enhancer-associated long noncoding RNAs (elncRNA) contribute to their cognate enhancer activity and gene expression regulation in cis. Recently, splicing of elncRNAs was shown to be associated with elevated enhancer activity. However, whether splicing of elncRNA transcripts is a mere consequence of accessibility at highly active enhancers or if elncRNA splicing directly impacts enhancer function, remains unanswered. We analysed genetically driven changes in elncRNA splicing, in humans, to address this outstanding question. We showed that splicing related motifs within multi-exonic elncRNAs evolved under selective constraints during human evolution, suggesting the processing of these transcripts is unlikely to have resulted from transcription across spurious splice sites. Using a genome-wide and unbiased approach, we used nucleotide variants as independent genetic factors to directly assess the causal relationship that underpin elncRNA splicing and their cognate enhancer activity. We found that the splicing of most elncRNAs is associated with changes in chromatin signatures at cognate enhancers and target mRNA expression. We provide evidence that efficient and conserved processing of enhancer-associated elncRNAs contributes to enhancer activity.

DOI: https://doi.org/10.1371/journal.pcbi.1009722
Chem Biol Interact. 2022 Jan 07. pii: S0009-2797(22)00011-4. [Epub ahead of print]353 109806

Inhibition of histone demethylase KDM4 by ML324 induces apoptosis through the unfolded protein response and Bim upregulation in hepatocellular carcinoma cells.

So Young Kim, Supyong Hwang, Bo Ra Lee, Jung A Hong, Young Hoon Sung, Inki Kim.

  Hepatocellular carcinoma (HCC) is an extremely aggressive malignancy that ranks as the sixth-leading cause of cancer-associated death worldwide. Recently, various epigenetic mechanisms including gene methylation were reported to be potential next era HCC therapeutics and biomarkers. Although inhibition of epigenetic enzymes including histone lysine demethylase 4 (KDM4) enhanced cell death in HCC cells, the detailed mechanism of cell death machinery is poorly understood. In this study, we found that ML324, a small molecule KDM4-specific inhibitor, induced the death of HCC cells in a general cell culture system and 3D spheroid culture with increased cleavage of caspase-3. Mechanistically, we identified that unfolded protein responses (UPR) were involved in ML324-induced HCC cell death. Incubation of HCC cells with ML324 upregulated death receptor 5 (DR5) expression through the activation transcription factor 3 (ATF3)-C/EBP homologous protein (CHOP)-dependent pathway. Moreover, we identified BIM protein as a mediator of ML324-induced apoptosis using CRISPR/Cas9 knockout analysis. We showed that the loss of Bim suppressed ML324-induced apoptosis by flow cytometry analysis, colony formation assay, and caspase-3 activation assay. Interestingly, BIM protein expression by ML324 was regulated by ATF3, CHOP, and DR5 which are factors involved in UPR. Specifically, we confirmed the regulating roles of KDM4E in Bim and CHOP expression using a chromatin immune precipitation (ChIP) assay. Physical binding of KDM4E to Bim and CHOP promoters decreased the response to ML324. Our findings suggest that KDM4 inhibition is a potent anti-tumor therapeutic strategy for human HCC, and further studies of UPR-induced apoptosis and the associated epigenetic functional mechanisms may lead to the discovery of novel target for future cancer therapy.

Keywords:  Bim; Death receptor 5; Hepatocellular carcinoma; Lysine demethylase 4; ML324; Unfolded protein response

DOI:  https://doi.org/10.1016/j.cbi.2022.109806
EMBO Mol Med. 2022 Jan 13. e14903

Inhibition of NPC1L1 disrupts adaptive responses of drug-tolerant persister cells to chemotherapy.

Zhe Zhang, Siyuan Qin, Yan Chen, Li Zhou, Mei Yang, Yongquan Tang, Jing Zuo, Jian Zhang, Atsushi Mizokami, Edouard C Nice, Hai-Ning Chen, Canhua Huang, Xiawei Wei.

  Entering a drug-tolerant persister (DTP) state of cancer cells is a transient self-adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug-resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA-seq revealed that these cells partially prevented chemotherapy-triggered oxidative stress by promoting NPC1L1-regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the -205 to -215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple-combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti-tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.

Keywords:  NPC1L1; cancer therapy; drug-tolerant persister state; multidrug resistance; oxidative stress

DOI:  https://doi.org/10.15252/emmm.202114903
Life Sci. 2022 Jan 11. pii: S0024-3205(22)00021-2. [Epub ahead of print] 120321

Role of histone demethylases and histone methyltransferases in triple-negative breast cancer: Epigenetic mnemonics.

Janice Jacson Mandumpala, Stephin Baby, Antriya Annie Tom, Chandraiah Godugu, Nagula Shankaraiah.

  Triple-negative breast cancer (TNBC) is a particularly lethal subtype of breast cancer owing to its heterogeneity, high drug resistance, poor prognosis and lack of therapeutic targets. Recent insights into the complexity of TNBC have been explained by epigenetic regulation and its ability to modulate certain oncogenes and tumour suppressor genes. This has opened an emerging area in anti-cancer therapy using epigenetic modulating drugs, highlighting the epigenetic reprogramming during tumorigenesis and tumour development. Histone methylation and demethylation are such dynamic epigenetic mechanisms mediated by histone methyltransferases (HMTs) and histone demethylases (HDMs), respectively. The interplay between HMTs and HDMs in histone methylation extrapolates their viability as druggable epigenetic targets in TNBC. In this review, we aim to summarize recent progress in the field of epigenetics focusing on HMTs and HDMs in TNBC development and their potential use in targeted therapy for TNBC management.

Keywords:  Epi-drugs; Epigenetics; Histone demethylases inhibitors; Histone methyltransferase inhibitors; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.lfs.2022.120321
Epigenomics. 2022 Jan 13.

The unfavorable clinical outcome of COVID-19 in smokers is mediated by H3K4me3, H3K9me3 and H3K27me3 histone marks.

Milad Shirvaliloo.

  Smoking could predispose individuals to a more severe COVID-19 by upregulating a particular gene known as mdig, which is mediated through a number of well-known histone modifications. Smoking might regulate the transcription-activating H3K4me3 mark, along with the transcription-repressing H3K9me3 and H3K27me3 marks, in a way to favor SARS-CoV-2 entry by enhancing the expression of ACE2, NRP1 and NRP2, AT1R, CTSD and CTSL, PGE2 receptors 2-4, SLC6A20 and IL-6, all of which interact either directly or indirectly with important receptors, facilitating viral entry in COVID-19.

Keywords:  COVID-19; H3K27me3; H3K4me3; HeK9me3; SARS-CoV-2; epigenetic gene regulation; epigenetics and disease; histone modifications; mdig; smoking

DOI:  https://doi.org/10.2217/epi-2021-0476
Front Cell Dev Biol. 2021 ;9 793428

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.

Miaomiao Huo, Jingyao Zhang, Wei Huang, Yan Wang.

  Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

Keywords:  clinical trails; epigenetic modifications; gut microbiota; metabolic enzymes; metabolic reprogramming

DOI:  https://doi.org/10.3389/fcell.2021.793428
Phys Rev E. 2021 Dec;104(6-1): 064403

Biomechanical model of cells probing the myosin-II-independent mechanosensing mechanism.

Yuqiang Fang, Yanbing Hu, Fei Cheng, Yuanzhu Xin.

Mechanosensing of cells to extracellular matrix (ECM) is highly active and plays a crucial role in various physiological processes. Growing numbers of studies provide evidence that cell sensitivity to ECM stiffness is a complex stress-strain feedback process. However, the mechanisms that rule this process are still not fully known. Here, an alternative mechanosensing scheme of cells, which is different from the previous myosin-II-based mechanisms, is proposed by employing the tension in cortical cytoskeletons (CSKs) as a force module to probe the substrate. The molecular mechanotransduction from cortical CSKs, through actin filaments and focal adhesions, and finally to the substrate, is mechanically modeled to scale the dynamic traction forces of cells. The developed model captures the characteristic spread of cells with respect to ECM stiffness whereby the spread is fully developed on a stiff substrate but not on a soft one. Furthermore, durotactic migration of cells on an elastic-gradient substrate is successfully modeled by the current method. The cells are concluded to migrate, actuated by the polarized traction forces from the stiffness gradient of the substrate and the stiffness matching between cells and substrate. Finally, the cells are proposed to actively target the preferred substrate by following a rule of mechanical matching between cells and substrate. This study provides a theoretical tool to advance our knowledge regarding the passive mechanical properties and the active sensing of cells, and further promotes the discovery of mechanosensing mechanisms as well as the material design for embryonic development and tissue homeostasis.

DOI: https://doi.org/10.1103/PhysRevE.104.064403